WO2005087198A1 - Processes for the preparation of solid dosage forms of amorphous valganciclovir hydrochloride - Google Patents
Processes for the preparation of solid dosage forms of amorphous valganciclovir hydrochloride Download PDFInfo
- Publication number
- WO2005087198A1 WO2005087198A1 PCT/IB2005/000615 IB2005000615W WO2005087198A1 WO 2005087198 A1 WO2005087198 A1 WO 2005087198A1 IB 2005000615 W IB2005000615 W IB 2005000615W WO 2005087198 A1 WO2005087198 A1 WO 2005087198A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- solid dosage
- dosage form
- valganciclovir hydrochloride
- process according
- amorphous
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 58
- ZORWARFPXPVJLW-MTFPJWTKSA-N [2-[(2-amino-6-oxo-3h-purin-9-yl)methoxy]-3-hydroxypropyl] (2s)-2-amino-3-methylbutanoate;hydron;chloride Chemical compound Cl.N1C(N)=NC(=O)C2=C1N(COC(CO)COC(=O)[C@@H](N)C(C)C)C=N2 ZORWARFPXPVJLW-MTFPJWTKSA-N 0.000 title claims abstract description 48
- 229960004983 valganciclovir hydrochloride Drugs 0.000 title claims abstract description 48
- 230000008569 process Effects 0.000 title claims abstract description 44
- 239000007909 solid dosage form Substances 0.000 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 239000008187 granular material Substances 0.000 claims description 28
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 24
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 22
- 238000002156 mixing Methods 0.000 claims description 15
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 15
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 15
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 15
- 239000011230 binding agent Substances 0.000 claims description 14
- 238000003801 milling Methods 0.000 claims description 14
- 239000000314 lubricant Substances 0.000 claims description 13
- 239000007884 disintegrant Substances 0.000 claims description 12
- 239000000945 filler Substances 0.000 claims description 12
- 235000019359 magnesium stearate Nutrition 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 12
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 10
- 229940079593 drug Drugs 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 10
- 238000001035 drying Methods 0.000 claims description 10
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 10
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 10
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 10
- 238000004513 sizing Methods 0.000 claims description 8
- 238000009491 slugging Methods 0.000 claims description 8
- 238000005056 compaction Methods 0.000 claims description 7
- 229920002472 Starch Polymers 0.000 claims description 6
- 229940032147 starch Drugs 0.000 claims description 6
- 239000002775 capsule Substances 0.000 claims description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 4
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 4
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 4
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 4
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 4
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 4
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 4
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 4
- 239000008107 starch Substances 0.000 claims description 4
- 235000019698 starch Nutrition 0.000 claims description 4
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 2
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
- 241000237858 Gastropoda Species 0.000 claims description 2
- 108010010803 Gelatin Proteins 0.000 claims description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 2
- 235000021355 Stearic acid Nutrition 0.000 claims description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 2
- 229930006000 Sucrose Natural products 0.000 claims description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 2
- 229940075614 colloidal silicon dioxide Drugs 0.000 claims description 2
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 2
- 229960000913 crospovidone Drugs 0.000 claims description 2
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 2
- 239000008121 dextrose Substances 0.000 claims description 2
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 2
- 239000008273 gelatin Substances 0.000 claims description 2
- 229920000159 gelatin Polymers 0.000 claims description 2
- 235000019322 gelatine Nutrition 0.000 claims description 2
- 235000011852 gelatine desserts Nutrition 0.000 claims description 2
- 229940071676 hydroxypropylcellulose Drugs 0.000 claims description 2
- 239000008101 lactose Substances 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 2
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 2
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 2
- 229940079832 sodium starch glycolate Drugs 0.000 claims description 2
- 239000008109 sodium starch glycolate Substances 0.000 claims description 2
- 229920003109 sodium starch glycolate Polymers 0.000 claims description 2
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 239000008117 stearic acid Substances 0.000 claims description 2
- 239000005720 sucrose Substances 0.000 claims description 2
- 239000000454 talc Substances 0.000 claims description 2
- 229910052623 talc Inorganic materials 0.000 claims description 2
- 239000001341 hydroxy propyl starch Substances 0.000 claims 2
- 235000013828 hydroxypropyl starch Nutrition 0.000 claims 2
- 239000002552 dosage form Substances 0.000 description 10
- 238000009490 roller compaction Methods 0.000 description 7
- 238000009826 distribution Methods 0.000 description 6
- 239000002245 particle Substances 0.000 description 6
- 229960002963 ganciclovir Drugs 0.000 description 4
- IRSCQMHQWWYFCW-UHFFFAOYSA-N ganciclovir Chemical compound O=C1NC(N)=NC2=C1N=CN2COC(CO)CO IRSCQMHQWWYFCW-UHFFFAOYSA-N 0.000 description 4
- 241000701022 Cytomegalovirus Species 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 238000007907 direct compression Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000005550 wet granulation Methods 0.000 description 3
- 208000030507 AIDS Diseases 0.000 description 2
- -1 L-valyl ester Chemical class 0.000 description 2
- WPVFJKSGQUFQAP-GKAPJAKFSA-N Valcyte Chemical compound N1C(N)=NC(=O)C2=C1N(COC(CO)COC(=O)[C@@H](N)C(C)C)C=N2 WPVFJKSGQUFQAP-GKAPJAKFSA-N 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 239000008199 coating composition Substances 0.000 description 2
- 238000007906 compression Methods 0.000 description 2
- 230000006835 compression Effects 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical group N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-Valine Natural products CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- 125000003580 L-valyl group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(C([H])([H])[H])(C([H])([H])[H])[H] 0.000 description 1
- 206010038910 Retinitis Diseases 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 229940057948 magnesium stearate Drugs 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 239000011812 mixed powder Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 238000012430 stability testing Methods 0.000 description 1
- 229960004274 stearic acid Drugs 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229940033134 talc Drugs 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229940010343 valcyte Drugs 0.000 description 1
- 229960002149 valganciclovir Drugs 0.000 description 1
- 229960004295 valine Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
- A61P31/22—Antivirals for DNA viruses for herpes viruses
Definitions
- the present invention relates to a process for the preparation of solid dosage forms of amorphous valganciclovir hydrochloride by dry method.
- Valganciclovir hydrochloride a prodrug of gancilcovir, is used in the treatment of cytomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome (AIDS) and for the prevention of CMV disease in kidney, heart and for kidney-pancrease transplant patients who are at high risk.
- CMV cytomegalovirus
- AIDS acquired immunodeficiency syndrome
- Valganciclovir hydrochloride is hydrochloride salt of the L-valyl ester of ganciclovir.
- Valganciclovir hydrochloride when administered orally is reported to have better bioavailability than ganciclovir given orally. It is known that the amorphous form of a drug may have certain advantages over the crystalline form, for example, amorphous form can be more soluble or can have a higher rate of solubility in water than the crystalline form and consequently the drug may show improved bioavailability, for example, due to the faster dissolution of the drug in the gastrointestinal fluid. It is with this view that we have prepared dosage forms comprising valganciclovir hydrochloride in which valganciclovir hydrochloride is present in the amorphous form.
- these dosage forms may further improve the oral bioavailability of valganciclovir and ultimately that of ganciclovir.
- amorphous valganciclovir hydrochloride as such is very fine and fluffy material, with relatively low bulk and tap density. This property can make it difficult to formulate into a dosage form with uniformity of weight, hardness, and other desirable tablet properties. Wet granulation needs to be avoided, as addition of a solvent along with subsequent removal in way of drying the granules at elevated temperatures may convert the amorphous form to crystalline form.
- the direct compression technique may not be desirable for a drug with a bulk density less than 0.2 g/cc, due to poor flow of the material leading to non-uniform die-fill and subsequent weight variation.
- direct compression could be a method of choice when the amorphous valganciclovir hydrochloride is so processed that it has a bulk density of at least 0.2 g cc or more. This can be achieved during chemical manufacturing by variation in the processing parameters or by a physical process of compaction and milling. There is a need for simple method of production, which does not require wet granulation with organic solvents or water and do not require an additional step of drying.
- processes for the preparation of solid dosage forms of amorphous valganciclovir hydrochloride wherein the processes comprise mixing amorphous valganciclovir hydrochloride with one or more pharmaceutically acceptable excipient(s) and forming into solid dosage forms.
- processes for the preparation of solid dosage forms of amorphous valganciclovir hydrochloride wherein the processes comprise mixing amorphous valganciclovir hydrochloride with one or more pharmaceutically acceptable excipient(s) and compressing into a tablet.
- processes for the preparation of solid dosage forms of amorphous valganciclovir hydrochloride comprising compacting valganciclovir hydrochloride alone or mixed with one or more pharmaceutically acceptable excipient(s) by, for example, roller compaction or slugging; sizing the compacts into granules by milling; optionally mixing the granules with one or more of pharmaceutically acceptable excipients and forming a solid dosage form.
- herein are provided processes for the preparation of solid dosage forms of amorphous valganciclovir hydrochloride wherein the processes comprise compacting valganciclovir hydrochloride alone or mixed with one or more pharmaceutically acceptable excipient(s) by, for example, roller compaction or slugging; sizing the compacts into granules by milling; optionally mixing the granules with one or more of pharmaceutically acceptable excipients and compressing into a tablet.
- methods of administering amorphous valganciclovir hydrochloride to a patient in need thereof as solid dosage forms prepared by a dry process Brief Description of the Drawings Fig.
- Solid dosage form comprising valganciclovir hydrochloride in amorphous form prepared by a dry process.
- the process is simple and economical as it does not require any solvents, as in the case of wet granulation processes, the most commonly followed process, which requires additional steps of drying the granules.
- the amorphous form resists conversion to a crystalline form by following the dry processes as described herein.
- solid dosage form as used herein includes granules, tablets or coated tablets and capsules filled with granules or tablets prepared as per the embodiments described herein.
- Particularly suitable solid dosage forms are tablets.
- the amorphous valganciclovir hydrochloride in the solid dosage form is present in a therapeutically effective amount.
- the drug may comprise from about lmg to about 1000 mg, for example, from about 50 mg to about 800 mg.
- the amorphous valganiclovir can be prepared by methods described in Indian Patent Application No.l052/DEL/2003 filed 28 August 2003. Additionally, other drugs in a therapeutically effective amount can also be combined with the present dosage forms.
- the pharmaceutically acceptable excipients are those known to the skilled in the art and may be selected from fillers, binders, disintegrants, glidant and lubricants. These excipients may be present intragranularly or extragranularly or both.
- the fillers may be selected from microcrystalline cellulose, mannitol, sucrose, lactose, dextrose, calcium carbonate, sorbitol and the like.
- the filler may be present in an amount of about 15% to about 60%, for example, from about 20% to 40% by weiglit of the dosage form.
- the binders may be selected from polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, starch and starch based binders, gelatin, gums and the like.
- the binder maybe present in an amount of about 0.1% to about 10%, for example, from about 1% to about 5% by weight of the dosage form.
- the disintegrant may be selected from crospovidone, croscarmellose sodium, starch, hydroxypropylcellulose, hydroxypropylmethylcellulose, gums, sodium starch glycolate and the like.
- the disintegrant maybe present in an amount of about 1% to about 40%), for example, from about 2% to about 20% by weight of the dosage form.
- the lubricants and glidants may be selected from talc, colloidal silicon dioxide, magnesium stearate, stearic acid and sodium stearyl fumarate. These maybe present in an amount of about 0.1 % to about 2% by weight of the dosage form.
- the compaction of the drug or the mixture comprising the drug and excipient(s) into compacts may be carried out by slugging or by roller compaction, particularly suitable is roller compaction.
- the roller compactor functions by uniformly applying pressure on a mixed powder blend by passing the blend between two counter-rotating rollers. The pressure imparted on the blend by the rollers compresses the powder into a compact, such as a sheet or ribbon, which is typically milled to produce granules.
- the valganciclovir hydrochloride can be mixed with one or more of pharmaceutical excipients such as filler, binder, disintegrant and lubricant described above in a suitable blender.
- the mixing time can vary from about 10 to 60 minutes.
- the resultant blend can either be directly compressed into solid dosage form or compacted by roller compaction.
- the resultant blend for compaction is subsequently transferred to a roller compactor in a known manner.
- the roller speed, roller gap width and force of compaction are then adjusted and the blend is fed through the roller compactor.
- the typical force and other conditions can be easily selected and adjusted by those skilled in the art.
- the compaction pressure may be between 25 to 75 bar, for example, between 35 to 55 bar.
- the rollers may be rotated at a speed of between 1 to 20 rpm, for example, between 2 to 10 rpm, or between 3 to 5 rpm.
- the compression force imparted on the blend by rollers converts the powdered form into a ribbon or compaction sheet.
- This compact sheet is fed to a mill, such as an oscillating mill, fitted with a screen.
- the screen can be selected with variable hole diameters depending upon the size of the granules required.
- the compact is converted into granules of the desired particle size distribution.
- the granules obtained as above may be filled into capsules or packed in a sachet.
- the granules can also be mixed with one or more of pharmaceutically acceptable excipients and compressed into tablets.
- slugging may be used for preparing solid dosage forms such as a tablet.
- the process is simple, low cost and effective. Slugging may be carried out by means of a tablet press.
- the drug either alone or mixed with other excipients is precompressed on a heavy duty press.
- the slug so formed is milled into granules and recompressed into tablet.
- the granules may also optionally be mixed with other extragranular excipients prior to compression into a tablet.
- Both the processes, i.e., roller compaction and slugging generate fines during the milling step. A portion of these fines can be mixed with granules and compressed into a tablet or can be easily recycled by collecting them and again compacted.
- the tablet must be of sufficient hardness to withstand the packaging, transport or coating process without chipping or breaking.
- the hardness of the tablets can be measured by known methods. The hardness should not be so high that it adversely affects disintegration and dissolution rates of the tablets.
- the hardness of these amorphous valganciclovir hydrochloride tablets is about 10 kP to about 30 kP, for example, about 15 kP to about 25 kP.
- Another measure of durability of the tablet is the test for friability. A friability values of about 1% is acceptable, but friability below about 0.8% is particularly suitable.
- the tablets prepared as per the process can have friability of less than 0.8%, for example, less than 0.5%.
- processes provided herein comprise mixing amorphous valganciclovir hydrochloride with one or of pharmaceutically acceptable excipients and compressing the blend into a tablet.
- processes provided herein comprise compacting amorphous valganciclovir hydrochloride alone or mixed with a lubricant using roller compactor; milling and sizing the compacts into granules with a desired particle size distribution; mixing with extragranular pharmaceutically acceptable excipient(s) and compressing into a tablet using appropriate tooling.
- processes herein comprise mixing amorphous valganciclovir hydrochloride, filler, binder, disintegrant and lubricant and compacting the mixture using roller compactor; milling and sizing the compacts into granules with a desired particle size distribution; mixing with lubricant and compressed into a tablet using appropriate tooling.
- processes provided herein comprise mixing amorphous valganciclovir hydrochloride, filler, binder, disintegrant and lubricant and compacting the mixture using roller compactor; milling and sizing the compacts into granules with a desired particle size distribution; mixing with one or more of filler, binder, disintegrant and lubricant and compressed into a tablet using appropriate tooling.
- processes provided herein comprise compacting amorphous valganciclovir hydrochloride alone or mixed with one or more of filler, binder, disintegrant and lubricant, milling and sizing the compacts into granules with a desired particle size distribution and filling into a capsule dosage form.
- processes provided herein comprise compacting amorphous valganciclovir hydrochloride alone or mixed with one or of pharmaceutically acceptable excipients by slugging; milling and sizing the slugs into granules with a desired particle size distribution; optionally mixing the granules with one or more of filler, binder, disintegrant and lubricant and compressed into a tablet.
- the solid dosage form When the solid dosage form is a tablet then it may additionally be coated with coating compositions like Opadry® AMB (with or without a non aqueous subcoat) sold by Colorcon to impart moisture protection on stability. Such a coating may comprise about 3 - 10%w/w of the tablet.
- the tablet may also be coated with coating compositions like Opadry® or Lustreclear® sold by Colorcon using non-aqueous or aqueous systems, preferably non-aqueous system to impart aesthetic appeal as well as a barrier to the external environment. Such a coating may comprise about 3-10%w/w of the tablet.
- the invention described herein can further be illustrated by the following examples but these do not limit the scope of the invention. EXAMPLE 1
- Valganciclovir hydrochloride (amorphous) was mixed in a blender with microcrystalline cellulose, cross-linked polyvinylpyrrolidone, polyvinylpyrrolidone and magnesium stearate and compressed into tablet using appropriate tooling.
- Valganciclovir hydrochloride (amorphous) was mixed with microcrystalline cellulose, cross-linked polyvinylpyrrolidone, polyvinylpyrrolidone and magnesium stearate and compacted with a roller compactor. The compacts were sized into granules by milling, mixed with magnesium stearate and compressed into tablet using appropriate tooling.
- Example 1 The tablets of Example 1 were subjected to accelerated stability testing. The tablets were kept at 40°C and 75% relative humidity for two months. The XRD data at the end of the two months period showed no change in amorphous nature in comparison to the initial scan of the amorphous valganciclovir hydrochloride, as shown in Fig. 1. EXAMPLE 3
- Valganciclovir hydrochloride (amorphous) and magnesium stearate were mixed in a blender and compacted using a roller compactor.
- the compacts were sized into granules by milling, mixed with microcrystalline cellulose, cross-linked polyvinylpyrrolidone, polyvinylpyrrolidone and magnesium stearate and compressed into tablet using appropriate tooling.
- Valganciclovir hydrochloride (amorphous) was mixed with microcrystalline cellulose, cross-linked polyvinylpyrrolidone, polyvinylpyrrolidone and magnesium stearate and compacted with a roller compactor. The compacts were sized into granules by milling, mixed with microcrystalline cellulose and magnesium stearate and compressed into tablet using appropriate tooling.
- Valganciclovir hydrochloride (amorphous) was mixed with microcrystalline cellulose, cross-linked polyvinylpyrrolidone, polyvinylpyrrolidone and magnesium stearate and compacted with a roller compactor.
- the compacts were sized into granules by milling, mixed with microcrystalline cellulose, cross-linked polyvinylpyrrolidone and magnesium stearate and compressed into tablet using appropriate tooling.
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
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DE602005008721T DE602005008721D1 (en) | 2004-03-10 | 2005-03-10 | METHOD FOR PRODUCING SOLID DOSAGE FORMS OF AMORPHEM VALGANCICLOVIR HYDROCHLORIDE |
US10/598,546 US20070292499A1 (en) | 2004-03-10 | 2005-03-10 | Processes for the Preparation of Solid Dosage Forms of Amorphous Valganciclovir Hydrochloride |
EP05708710A EP1725217B1 (en) | 2004-03-10 | 2005-03-10 | Processes for the preparation of solid dosage forms of amorphous valganciclovir hydrochloride |
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IN410DE2004 | 2004-03-10 | ||
IN410/DEL/2004 | 2004-03-10 |
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WO2005087198A1 true WO2005087198A1 (en) | 2005-09-22 |
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PCT/IB2005/000615 WO2005087198A1 (en) | 2004-03-10 | 2005-03-10 | Processes for the preparation of solid dosage forms of amorphous valganciclovir hydrochloride |
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Country | Link |
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US (1) | US20070292499A1 (en) |
EP (1) | EP1725217B1 (en) |
AT (1) | ATE403418T1 (en) |
DE (1) | DE602005008721D1 (en) |
WO (1) | WO2005087198A1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008071573A3 (en) * | 2006-12-13 | 2008-11-27 | Hoffmann La Roche | Powder formulation for valganciclovir |
CN104055746A (en) * | 2014-07-12 | 2014-09-24 | 石家庄科仁医药科技有限公司 | Valganciclovir hydrochloride coated tablet combination |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
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US20100298564A1 (en) * | 2009-05-25 | 2010-11-25 | Venu Nalivela | Preparation of amorphous valganciclovir hydrochloride |
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US6248363B1 (en) * | 1999-11-23 | 2001-06-19 | Lipocine, Inc. | Solid carriers for improved delivery of active ingredients in pharmaceutical compositions |
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WO2004010998A1 (en) * | 2002-07-25 | 2004-02-05 | Pharmacia Corporation | Sustained-release tablet comprising reboxetine |
US20040062805A1 (en) * | 1999-03-31 | 2004-04-01 | Vandecruys Roger Petrus Gerebern | Pregelatinized starch in a controlled release formulation |
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US5292534A (en) * | 1992-03-25 | 1994-03-08 | Valentine Enterprises, Inc. | Sustained release composition and method utilizing xanthan gum and an active ingredient |
US5856481A (en) * | 1994-07-28 | 1999-01-05 | Syntex (U.S.A.) Inc. | 2-(2-amino-1,6-dihydro-6-oxo-purin-9-yl)methoxy-1,3-propanediol derivative |
US6660303B2 (en) * | 1999-12-06 | 2003-12-09 | Edward Mendell & Co. | Pharmaceutical superdisintegrant |
WO2005021549A1 (en) * | 2003-08-28 | 2005-03-10 | Ranbaxy Laboratories Limited | Amorphous valganciclovir hydrochloride |
US8771735B2 (en) * | 2008-11-04 | 2014-07-08 | Jazz Pharmaceuticals, Inc. | Immediate release dosage forms of sodium oxybate |
-
2005
- 2005-03-10 EP EP05708710A patent/EP1725217B1/en active Active
- 2005-03-10 AT AT05708710T patent/ATE403418T1/en not_active IP Right Cessation
- 2005-03-10 US US10/598,546 patent/US20070292499A1/en not_active Abandoned
- 2005-03-10 DE DE602005008721T patent/DE602005008721D1/en active Active
- 2005-03-10 WO PCT/IB2005/000615 patent/WO2005087198A1/en active IP Right Grant
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
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US6395029B1 (en) * | 1999-01-19 | 2002-05-28 | The Children's Hospital Of Philadelphia | Sustained delivery of polyionic bioactive agents |
US20040062805A1 (en) * | 1999-03-31 | 2004-04-01 | Vandecruys Roger Petrus Gerebern | Pregelatinized starch in a controlled release formulation |
US6248363B1 (en) * | 1999-11-23 | 2001-06-19 | Lipocine, Inc. | Solid carriers for improved delivery of active ingredients in pharmaceutical compositions |
WO2004010998A1 (en) * | 2002-07-25 | 2004-02-05 | Pharmacia Corporation | Sustained-release tablet comprising reboxetine |
Cited By (6)
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WO2008071573A3 (en) * | 2006-12-13 | 2008-11-27 | Hoffmann La Roche | Powder formulation for valganciclovir |
KR101116553B1 (en) | 2006-12-13 | 2012-03-13 | 에프. 호프만-라 로슈 아게 | Powder formulation for valganciclovir |
CN101541310B (en) * | 2006-12-13 | 2012-11-07 | 弗·哈夫曼-拉罗切有限公司 | Powder formulation for valganciclovir |
US8889109B2 (en) | 2006-12-13 | 2014-11-18 | Hoffman-La Roche Inc. | Pharmaceutical dosage forms comprising valganciclovir hydrochloride |
US9642911B2 (en) | 2006-12-13 | 2017-05-09 | Hoffmann-La Roche Inc. | Pharmaceutical dosage forms comprising valganciclovir hydrochloride |
CN104055746A (en) * | 2014-07-12 | 2014-09-24 | 石家庄科仁医药科技有限公司 | Valganciclovir hydrochloride coated tablet combination |
Also Published As
Publication number | Publication date |
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EP1725217B1 (en) | 2008-08-06 |
US20070292499A1 (en) | 2007-12-20 |
EP1725217A1 (en) | 2006-11-29 |
ATE403418T1 (en) | 2008-08-15 |
DE602005008721D1 (en) | 2008-09-18 |
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